Maternal diabetes is major cause of birth defects and a contributing factor to the development of diabetes in the offspring. A hyperglycemic environment during pregnancy significantly increases the rat of malformation and resorption in the fetus. In addition, children and adults from diabetic mothers have a markedly higher rate of Type 2 diabetes. The most widely proposed hypothesis for damage is free radical (oxidative) stress to the developing fetus. Based on this hypothesis, clinical trials of antioxidants are being proposed for antioxidant treatment of diabetic mothers. However, there are problems with the current evidence for this hypothesis, which we will address in our proposed studies. Most of the support for the antioxidant hypothesis derives from treatment of diabetic rats with antioxidant vitamins, E and C. Because these drugs are delivered systemically it is impossible to determine if the protective effect is exerted at the level of the fetus or the mother, since both are subject to hyperglycemia and subsequent oxidative stress. To overcome this limitation we will produce antioxidant transgenes that will be expressed exclusively in the developing embryo. An additional problem with prior studies is that they have been performed using streptozotocin induced diabetes. Streptozotocin is a powerful oxidant and its damaging effects are not confined to the pancreatic beta cell. To overcome this limitation we will use the OVE26 transgenic model of diabetes. In these mice diabetes is induced by a transgene that is absolutely confined to the pancreatic beta cell, eliminating any potential direct damaging effects on the fetus. The impact of maternal diabetes on the ultimate development of Type II diabetes in the offspring has recently been recognized. Until now most attention has been paid to the role of insulin resistance. However, impaired insulin secretion is at least as crucial to the development of Type II diabetes and diabetes will not develop unless secretion fails. The insulin secretin beta cell is one of the most sensitive cells in the body to free radical damage. We will apply our expertise in pancreatic islet function to determine if insulin secretion is impaired in the offspring of OVE26 diabetic mothers and to examine whether a fetal antioxidant transgene can protect from the development of Type II diabetes in the offspring. To test our hypothesis that fetal oxidative stress leads to congenital malformations and to long term damage to insulin secretion we will carry out the following Specific Aims: 1. Evaluate developmental aberrations in the offspring of diabetic OVE26 mice. 2. Characterize glucose homeostasis and pancreatic islet function in the offspring of diabetic OVE26 mice. 3. Produce transgenic mice that over-expressing antioxidants metallothionein (MT) and Mn superoxide dismutase (MnSOD) during embryonic and fetal development. 4. Determine if antioxidant transgenes can reduce maternal diabetes induced damage to fetal development and islet function. Completion of these Specific Aims will provide a definitive genetic test of the role of oxidative damage to the offspring. They will also provide a much-improved model of maternal diabetes, which is amenable to modern genetic manipulation.